L-methylbarbitcric acid derivatives



and useful 5,5 disubstituted l-methylbarbituric 10, it being understood that R has a carbon atom monium, monoalkyl ammonium, dialkyl am- Patented July 25, 1944 l-METHYLBARBITURIO ACID DERIVATIVE AND THEE SALTS Lewis A. Walter, East Orange, N. 1., assignor to The Maltbie Chemical Company, Newark, N. J., a corporation of New Jersey No Drawing. Application February 28, 1942, Serial No. 432,890

acclaim. (01. 260-257) The present invention relates to certain new tion, and of their preparation:

acids, and their salts, having the formula: EXAMPLE 1 5 1 -methyl-5-ethylthiomethylen'e-5-methyl R s CH1 I o O-N barbituric acid To 1.1 moles of sodium, dissolved in 500 cc.

of absolute alcohol, and 1.0 mole of ethylthiomethylene methyl malonic ester, 1.1 moles of methylurea are added. This mixture is refluxed "on a steam bath for about 12 hours, the alcohol is removed by vacuum distillation, and the residue is dissolved in about 600 cc. of water. The resulting aqueous solution is then extracted with ether, and the aqueous layer is separated and acidified, yielding a precipitate of 1-methyl-5- ethylthiomethylene--methyl barbituric acid,

' which is then filtered off and purified by crystallization from alcohol. The product has a melting point of approximately 104-105 C. (uncor- 'rected), and is represented by the following 11 \CONX wherein R and R are hydrocarbon groups, either saturated or unsaturated, and either the same or different, and each of which contains not more than six carbon atoms, and wherein the sum of the carbon atoms in R and R, does not exceed attached directly to the sulfur of the thiomethyl-.,, one group and R has a carbon atom attached directly to the carbon atom forming the barbiturlc acid nucleus; and wherein X is a member selected from the group consisting of hydrogen, alkalimetal, an equivalent of alkaline earth metal, am

monium, alkanol ammonium and an equivalent iormula: of alkylene diammonium. (33 5011, c0 0 These novel l-methylbarbituric acid com- C 0 (2) pounds and their salts, when tested pharmacologically, have been found to possess useful and GHQ COTNH valuable hypnotic and sedative properties, mals- EXAMPLE 2 ing them valuable for many medical purposes. The compounds are, in general, white, and are generally crystalline solids.

As at present advised, what is in general a preferred procedure for preparation of my novel 1 -methyl-5-ethylthiom'ethylene-5-isopropyl barbitun'c acid To 1.1 moles of sodium, dissolved in 500 cc. of absolute alcohol, and 1.0 mole of ethylthio- 1-methylbarbituric acids from disubstituted methylene isopropyl malonic ester, 11 moles of malonic esters is described below; but other methylurea are added- The mixture is refluxed methods of ynthesis may s be used, Such as, on a steam bath for about ,12 hours, the alcohol for example, by using the disubstituted is removed by vacuum distillation, and the residue acetic ester instead of the disubstituted malonic is dissolved in about of t The resultt The former method f synthesis is m ing aqueous solution is extracted with ether and h t d as follows; l the aqueous layer is separated and acidified,

A disubstituted malonic ester (such as may be 40 yielding a p e p tate 0f -methy1-5-ethy thi0- prepared, for example, in accordance with applil methylene-S-isopropyl barbituric acid, which is cation Serial No. 432,887, filed February 28,1942) then filtered Off and Purified by crystallization is condensed with N-methylureain the presence from almholh Product has a melting Point of sodium ethylate in an organic solvent such as, of approximately (un'corrected), and for example, absolute alcohol, under conditions 7, is represented by the following mlmulai such as those hereafter specifically illustrated.

When the reaction is completed, the solvent is v C (3) removed by vacuum distillation and the residue l is dissolved in water. The aqueous solution is (OHmCH CO NH then extracted with ether, and is separated from X LE 3 the ether layer and acidified, yielding a precipitate of the desired l-methylbarbituric acid, which may then be filtered oii and purified by crystalbmnwnc acid lization from a suitable solvent suchas ethanol. To 1.1 moles of sodium, dissolved in 500 cc.

The following specific examples are illustrative of absolute alcohoLiand 1.0 mole of isopropyl- 1 =methyl-5 -isopropylthiometl iylene-5-ethyl of the novel compounds according to my inven- I from alcohol.

thiomethylene ethyl malonic ester, 1.1 moles of methylurea are added. The mixture. is refluxed on a steam bath for about 12 hour-s, the alcohol is removed by vacuum distillation, and the residue is dissolved in about 600 cc. of water. The re-. 'sulting aqueous solution is extracted with ether, and the aqueous layer is separated and acidified,

yielding -aprecipitate of 1-methy1-5-isopropylthiomethylene-5-ethyl barbituric acid, which is then filtered 01! and purified by crystallization from alcohol: The product has a melting point of approximately 87-88.5 C. (uncorrected), and is represented by the following formula:

(CH:):GHSCH:\ CO-N-CHa ExlmrLa 4 1-methyl-S-n-Mtylthiomethylene-5-methyl barbituric acid To 1.1 moles of sodium, dissolved in 500 cc. of absolutealcohol, and 1.0, mole of n-butylthiomethylene methyl malonic ester, 1'.1 moles of methylurea are added. The mixture is refluxed on a steam bath for about 12 hours, the-alcohol is removed by vacuum distillation, and the residue is dissolved in about 600 cc. of water. The resulting aqueous solution .is extracted with ether, and the aqueous layer is' separated and acidified, yielding a precipitate of 1-methyl 5-n-butylthlomethylene-5-methy1 barbituric. acid, which is then filtered ofi and purified by crystallization The product has a melting point" of approximately 75-77 C. (uncorrected), and

is represented by the following formula:

lowing list being illustrative and not exclusive i-mothylbarblturio acid SALTS or m Novar. 1-METHYLBARBITURIC Acrn DERIVATIVES Many sodium salts of the l-methylbarbituric acids described above may be prepared by dissodium salt in amorphous form.

Other alkali-metal salts may also be derived by a similar procedure.

The sodium salts of my novel 1-methylbarbituric acid derivatives have been found to be readily soluble in water, and their aqueous solutions are alkaline in reaction. When administeredorally or hypodermically in proper dosage they are good and useful hypnotics or sedatives, and range in duration of action from long to ultra-short acting.

Calcium salts may be prepared by treating an absolute'alcohol solution of the sodium salt with the metathetical amount of alcoholic calcium chloride, filtering off the precipitated sodium chloride and concentrating the alcoholic solution to yield the calcium salt. v

The ammonium, alkyl and alkanol ammonium salts may be prepared by dissolving the corresponding l-methylbarbituric acid in an excess of ammonia or amine and subsequently removing the excess quantity of base.

In the following claims it is to be understood that l-methylbarbituric acid derivative and similar expressions, includes, also, the salts of such derivatives, such as, for example, the salts described above.

The examples given above, and illustrative processes for their production, include the best embodiments of my present invention now known to me; but it is to be understood that'the invention is not necessarily I or specifically limited thereto and may, under proper conditions, have other embodiments, produced in other ways, with- (311: RSCH OO-N k Aglproximate O\ I0 111 1 1613011112, 7 11 oo-mzr (uncorrected) wherein:

Ris- B'isout departure from the spirit of the invention, and within the scope of the following claims.

I claim:

1;- As a new and useful composition of matter, a 5,5 disubstituted l-methylbarbituric .acid .derivative having the formula:

, wherein R and R are hydrocarbon groups, each of which contains not more than six carbon atoms, and wherein the sum of the carbon atoms in R and B does not exceed 10, R has a carbonr atom attached directly to the sulfur of the thiomethylene group, and R has a carbon atom attached directly to the carbon atom forming the barbituric acid nucleus; and wherein x is a member selected from .the group consisting of hydrogen, alkali-metal, an equivalent of alkaline 1 in which at least one of the R and R groups is a primary hydrocarbon group.

4. A composition 01' matter according to claim 1 in which at least one of the R and R groups is a primary hydrocarbon group and X repre sents hydrogen.

5. A composition of 6. A composition of matter according to claimr 1 in which R is a-primary hydrocarbon group and R is a saturated hydrocarbon group.

1'1. A composition of matter according to claim 1 in which R is a primary hydrocarbon group. R is a saturated hydrocarbongroup, and X represents hydrogen. I

'8. A composition of matter 1 in which R is a primary hydrocarbon group and X represents hydrogen.

9. A composition of matter according to claim 1 in which R' is a primary hydrocarbon group.

10. A composition of matter according to claim 1 in which R is a primary hydrocarbon group and X represents hydrogen.

11. A compositionoi matter according to claim 1 in which R and R are both primary hydrocarbon groups. V

12. A composition of matter according to claim 1 in which R and R are both primary hydrocarbon groups and 1: represents hydrogen.

matter according to claim 1 in which R is a primary hydrocarbon group.

according to claim 25 methylurea in the presence of sodium ethyiate v met!ly'lliarliiitlli'ic acid.

13. A composition of matter according to claim 1 in which R is a primary hydrocarbon group and R is a secondary hydrocarbon group.

) 14. A composition of matter according to claim v1 in which R is a primary hydrocarbon group, R a secondary hydrocarbon group, and X represents hydrogen. L

15. A composition of matter according to claim 1 in which R is a secondary hydrocarbon group and R is a primary hydrocarbon group.

16. A composition of matter according to claim 1 in which R is a secondary hydrocarbon group, R aprimary hydrocarbon group, and X represents hydrogen.

1'7. 5-ethyithiomethylene-5-isobutyl. l-methylbarbituric acid. Y

18. 5-ethylthiomethylene-:i-secondary butyl 1- 19. 5-isopropylthiomethylene-5-ethyl l-methylbarbitm'ic-acid.

20. The process of producing 15,5 disubstituted I-rnethylbarbituric acid derivative according to .claim 1, which comprises condensing a corresponding disubstituted malonic ester with N- in an organic solvent.

. LEWIS A. WALTER.

CERTIFICATE OF CORRECTION.

Patent No. 2,551+,255. July 25, 191m.

LEWIS A. WALTER.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: Page 1, sec-- 0nd column, line 14.6, Example 2, for that portion of the formula reading "C H GSH read --C H SCH and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this lhth day of November, A. D. 19%.

Leslie Frazer (Seal) Acting Commissioner of Patents. 

